Drugs - Real World Outcomes (2016) 3:83–88 DOI 10.1007/s40801-016-0060-y
ORIGINAL RESEARCH ARTICLE
Haloperidol Use Among Elderly Patients Undergoing Surgery: A Retrospective 1-Year Study in a Hospital Population Harmke Nijboer1 • Geert Lefeber1 • Alidair McLullich1 • Barbara van Munster1
Published online: 3 March 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com
Abstract Background Haloperidol, frequently used for delirium, can lead to serious side effects, of which QTc prolongation is the most worrisome since it is associated with an increased risk of fatal cardiac arrhythmia. Objectives The aim of this study was to measure the frequency of haloperidol use after procedures in patients aged C65 years in a hospital in the Netherlands. Methods This was a retrospective study among patients hospitalized in the Netherlands who were aged C65 years and who underwent a procedure between January 2008 and January 2009. The hospital’s electronic drug database was used to identify the use of haloperidol during hospital admission. Results A total of 7782 procedures took place in 5946 elderly patients, and 1357 patients were readmitted for a second procedure in the same year. The overall frequency of haloperidol use was 5.4 %. Procedures were classified as elective (90 %) and as major (18 %). A total of 28 % (n = 570) of patients who underwent acute procedures and 24 % (n = 1086) of patients who underwent major procedures received haloperidol. Patients receiving haloperidol had a significantly longer hospital stay (14 vs. 1 day, p \ 0.001) than patients without haloperidol. Haloperidol users were more likely to have more than one intervention than nonusers (16.0 vs. 1.7 %, p \ 0.001). In multivariable analysis, haloperidol use was associated with older age (odds ratio [OR] 1.09; 95 % confidence interval [CI] 1.07–1.11, p \ 0.001), acute surgery (OR 2.09; 95 % CI 1.65–2.94,
& Harmke Nijboer [email protected] 1
Catharina Hospital, Eindhoven, Brabant, The Netherlands
p \ 0.001), and major procedures (OR 15.4; 95 % CI 11.5–21.5, p \ 0.001). Conclusion We show a frequency of haloperidol use of 5.4 %. Based on this high frequency, surveillance of adverse events in hospital should be performed systematically, particularly in the high-risk population that undergoes acute major surgery.
Key Points The frequency of haloperidol use among hospitalized patients in the Netherlands aged C65 years who underwent a procedure between January 2008 and January 2009 was over 5 %. The percentage of haloperidol users is higher in older patients undergoing acute or major procedures. Patients using haloperidol experienced a longer hospital stay in this study and are known to have a higher risk of adverse events in the literature.
1 Introduction In 2005, the US FDA warned clinicians against prescribing antipsychotic medications to patients with dementia-related psychosis, because it would expose patients to an increased risk of death [1]. Mittal et al. [2] showed a 1.3 to 2.0-fold increased risk of stroke and a 1.2 to 1.6-fold increased risk of mortality; these risk ratios are comparable for all antipsychotics. Known immediate side effects of antipsychotics include somnolence, urinary tract infection, urinary
84
incontinence, extrapyramidal symptoms, or abnormal gait [3–6]. Antipsychotics are prescribed for many different symptoms and diseases, such as anxiety, psychosis due to schizophrenic disease or depression, and behavioral disturbance in dementia or delirium. Hospitalized patients with delirium may have a similar or even higher potential for adverse side effects from antipsychotics than more stable patients. The most important known risk factors for postoperative delirium are older age and cognitive or functional impairment [7]. Many older patients with delirium also have dementia; they also usually have an acute medical illness and multiple comorbidities, and are often taking drugs that increase the QTc interval. Yet this issue remains unaddressed, because no published, adequately powered, double-blind, randomized, placebo-controlled trials have examined the safety of antipsychotics in the management of delirium [8]. In addition, no specific recommendations exist for patients with delirium as well as dementia. Prevalence estimates for delirium during a hospital admission are 10–30 %; thus, it is reasonable to assume that this condition is the single most common cause for the administration of haloperidol in a hospital setting [9, 10]. The scientific evidence for the efficacy of haloperidol in treating delirium is based on a few studies [10]. Five studies evaluated the side effects of haloperidol versus various neuroleptics (e.g., risperidone, olanzapine, quetiapine, and ondansetron) and showed no significant differences in the treatment response for delirium symptoms [11–15]. The 2010 UK National Institute for Health and Care Excellence (NICE) guideline on delirium, which took into account the evidence available at that time, advised limiting the use of antipsychotics for individuals with delirium in distress or at risk to themselves or others. Furthermore, it should be prescribed only after nonpharmacological interventions have been tried, and then only in the lowest possible dose and for the shortest possible time period [16]. The aim of this study was to measure the frequency of haloperidol use after procedures in patients aged C65 years in a hospital in the Netherlands. A prerequisite for assessing the risks associated with antipsychotic use in hospitalized patients is to have systems that record the use of these drugs. To address the above gap in the literature, we used electronic pharmacy records to determine the proportion of hospitalized patients aged C65 years administered haloperidol after surgical procedures. We studied haloperidol because it is the first-choice medication for delirium in the Netherlands [17].
H. Nijboer
2 Methods 2.1 Patients All patients aged C65 years who underwent a surgical procedure in the Jeroen Bosch hospital in s–Hertogenbosch in the Netherlands in the period between 1 January 2008 and 1 January 2009 were included. This hospital has 750 beds and is a non-academic, regional teaching hospital with 21 separate medical training specialties. The surgical specialties were gynecology, orthopedics, general surgery, urology, ophthalmology, otorhinolaryngology, oral surgery, neurosurgery, and plastic or reconstructive surgery. 2.2 Study Design Haloperidol administration during admission was identified using the electronic hospital drug database. Inclusion criteria included patients who took this medication for at least 1 day during their admission period. In the Netherlands, the conventional starting dose for haloperidol is 1 mg. Minor procedures were defined as procedures for which patients were admitted for less than 6 days, and major procedures were defined as a stay longer than 6 days. Procedures were categorized as either acute or elective based on the reason for admission, as classified by the International Statistical Classification of Diseases and Related Health Problems – 9th revision (ICD-9). 2.3 Statistical Analysis We used the Statistical Package for the Social Sciences (SPSS, version 19.0, Chicago, IL, USA) for data analysis. We used t-tests and Mann–Whitney U tests to test for differences in characteristics in patients with and without haloperidol use. Variables that were not normally distributed were expressed as median scores and interquartile ranges. A two-tailed criterion of p \ 0.05 was considered statistically significant. We performed univariate and multivariate logistic regression analyses, where haloperidol use was the dependent variable, and age, acute versus elective surgery, minor versus major procedures, and surgical specialty were the independent variables.
3 Results A total of 7782 procedures occurred in 5946 patients; 145 patients underwent a second procedure during their first admission, and 1357 patients were admitted for at least one additional procedure in the same year. The characteristics of the patients who did and did not use haloperidol are
Haloperidol Use Among Elderly Patients Undergoing Surgery
85
presented in Table 1. The overall incidence of haloperidol use related to the first procedure in the first admission was 5.4 %. Of these, 323 patients (12 %) received haloperidol throughout the complete admission period. Those administered haloperidol were significantly older (81.2 vs. 74.4 years, p \ 0.001). In acute procedures (n = 570), the percentage of haloperidol use was 28.0 versus 3.1 % in the 5376 elective procedures (p \ 0.001). In major procedures (n = 1086), the percentage was 24.0 versus 1.3 % in 4960 minor procedures (p \ 0.001). Patients who received haloperidol had a significantly longer hospital stay (14 vs. 1 day, p \ 0.001) than patients who did not receive haloperidol. Haloperidol users more often underwent more than one procedure (e.g., they underwent two operations or a biopsy followed by an operation during the admission period [16.0 vs. 1.7 %, p \ 0.001]) than non-users, but they were less frequently readmitted for a second procedure (12 vs. 23 %, p \ 0.001). An overview of the most common procedures per specialty is presented in Table 2; 90 % of procedures were elective and 18 % were major. A total of 29 % of acute procedures and 45 % of major procedures were performed in general surgery. Of these, 15 % of patients received haloperidol. Ophthalmologic surgery was the most frequent type of surgery (n = 1865; 31.4 %), and the majority of the ophthalmologic interventions were cataract operations (89.5 %). These were classified as minor procedures, with a haloperidol usage of 0.4 %. Haloperidol use in patients admitted with a fracture was acute: 30 % in surgical Table 1 Characteristics of patients who did and did not receive haloperidol
Variables
patients and 34 % in orthopedic patients. Haloperidol use in orthopedics was 6.4 %, in plastic surgery 0.3 %, in urology 2.4 %, and in gynecology 1.7 %; no patients in the otorhinolaryngology received haloperidol. The odds ratio (OR) of haloperidol administration upon second admission if patients had already been administered haloperidol at first admission was 55 (95 % confidence interval [CI] 27–116). Table 3 shows the results of the multivariate analysis. Haloperidol use was strongly associated with specialty, specifically general surgery (OR 6.4, 95 % CI 4.0–10.1, p \ 0.001), acute procedures (OR 1.5, 95 % CI 1.1–2.1, p \ 0.001), major procedures (OR 8.3, 95 % CI 5.9–11.5, p \ 0.001), and older age (OR 1.1, 95 % CI 1.08–1.12, p \ 0.001).
4 Discussion In this descriptive study of haloperidol use in a hospital population of surgical patients (N = 5946) treated over the course of 1 year in a single large hospital in the Netherlands, we found an overall frequency of haloperidol administration of 5.4 %. The hospital is representative of large teaching hospitals in the Netherlands. Haloperidol use in acute and major surgery was much higher than in elective and minor surgery; at least one-quarter of patients who fell into either category received this drug. The fact that haloperidol administration was associated with older age, acute procedures, and major procedures, which are all
Haloperidol (N = 323)
No haloperidol (N = 5623)
p value \0.001
Age (years)
81.2 (65–101)
74.4 (65–104)
Male sex (%)
145 ± 45
2409 ± 43
Ophthalmology
7 ± 2.2
1858 ± 33
General surgery Orthopedic surgery
230 ± 71 66 ± 20
1269 ± 23 962 ± 17
Plastic surgery
2 ± 0.6
632 ± 11
0.47 \0.001
Specialty (%)
Urology
14 ± 4.3
578 ± 10
Gynaecology
4 ± 1.2
226 ± 4.0
Otorhinolaryngology
0±0
70 ± 1.2
Othera
0±0
28 ± 0.5
Acute procedure (%)
157 ± 49
413 ± 7.3
\0.001
Major procedure (%)
261 ± 81
825 ± 15
\0.001
Length of stay
14 (2–133)
1 (1–142)
\0.001
C1 Intervention (%)
52 ± 16
93 ± 1.7
\0.001
C1 Admission (%)
39 ± 12
1318 ± 23
\0.001
Data are presented as mean ± standard deviation for continuous variables with a normal distribution or as median (interquartile range) for variables that are not normally distributed a
‘Other’ includes cardiology, neurosurgery, and oral surgery
86 Table 2 Characteristics of the most common surgical procedures, by specialty
H. Nijboer
Variables
Procedures
Acute (%)
Ophthalmology
1865
1 (0.1)
Senile cataract
1670 (89.5 %)
General
1499
Fracture reposition
318 (21.2 %)
Biopsya
240 (16 %)
Digestive tract operations
218 (14.6 %)
Vascular intervention
200 (13.3 %)
Inguinal hernia operation
140 (9.3 %)
Shunt construction
38 (2.5 %)
Orthopedics
1028
Osteoarthrosis surgery
86 (8.4 %)
Removal of plates and correction material
83 (8 %)
Hand surgery due to mononeuritis Biopsy
634
54 (8.5 %)
Other
386 (60.9 %) 592
Urethrocystoscopy
320 (54.1 %)
Prostatectomy
138 (23.3 %)
Biopsy
34 (5.4 %)
Gynecology
230
Biopsy
91(39.6 %)
Genital prolapse surgery
78 (33.9 %)
Otorhinolaryngology
70
Sinusitis surgery
20 (28.6 %)
Septum rhinoplasty
8 (11.4 %)
Correction nasal polyp Otherb
0.4 %
430 (29)
674 (45)
15.3 %
110 (11)
250 (24)
6.4 %
8 (1.3)
16 (2.5)
0.3 %
15 (2.5)
70 (12)
2.4 %
3 (1.3)
69 (30)
1.7 %
124 (19.6 %) 36 (5.4 %)
Eye correction surgery Urology
3 (0.2)
Haloperidol Use
478 (46.5 %)
Fracture reposition Plastic surgery
Major (%)
0
1 (1.4)
0
3 (11)
3 (11)
0
9 (12.9 %) 28
a
Biopsy in general surgery includes pulmonary biopsy, lymph nodular explorations, benign exploration of thyroid pathology, rectal polyp excisions, and mamma incision biopsy
b
‘Other’ includes neurosurgery and oral surgery
established risk factors for delirium, suggests that delirium could be the most important indication for its prescription [18]. However, we do not know the indication of haloperidol use, and the known risk factors for delirium— such as operative stress and other drugs used peri- and postoperatively—are not measured in our database. Furthermore, in our study population, a large group of patients were ophthalmologic patients (n = 1865), most of whom underwent a cataract procedure; this type of procedure is known to have a low delirium prevalence. It is possible that approximately 0.1 % of patients received haloperidol 1 mg/day prior to procedures if it was known that they had a medical history of serious delirium. Indeed, a 5.4 % haloperidol administration level is consistent with the typical delirium rates in these groups, as
reported in the international literature [16, 17]. Additionally, the multivariate analysis showed that haloperidol use was associated with longer hospital stay, which might be another indirect clue that patients who received haloperidol experienced delirium because delirium is known to be associated with a prolonged hospital stay [19]. Alternatively, the use of haloperidol itself may have contributed to the length of stay. More broadly, this study shows that large numbers of older people received haloperidol during their hospitalisation for surgery. This level of haloperidol use is notable given the lack of strong evidence for the benefits of this drug in the treatment of delirium. No previous study has investigated the appropriate antipsychotic dosage levels for delirium, and we believe different countries have different antipsychotic dosage strategies [9].
Haloperidol Use Among Elderly Patients Undergoing Surgery
87
Table 3 Univariate and multivariate analysis of the factors associated with haloperidol use in surgical patients aged [65 years Factor
Univariate analysis OR (95 % CI)
p value
Multivariate analysis OR (95 % CI)
p value
Age (years)
1.12 (1.11–1.14)
\0.001
1.1 (1.08–1.12)
\0.001
Specialty (%) Othera
Reference
General surgery
22.8 (15.2–34.1)
\0.001
6.4 (4.0–10.1)
\0.001
Orthopedic surgery
8.6 (5.5–13.6)
\0.001
4.0 (2.4–6.5)
\0.001
Acute procedure (%)
11.9 (9.38–15.2)
\0.001
Major procedure (%)
24.5 (18.4–32.6)
0.004
1.5 (1.1–2.1)
\0.001
8.3 (5.9–11.5)
\0.001
CI confidence interval, OR odds ratio a
All surgeries except general or orthopedic surgery
Importantly, in the last 10 years, more studies have identified a number of risks associated with prescribing antipsychotic drugs during hospital stay, such as a higher risk of pneumonia [20] and or cerebrovascular events. This risk is present even during the first week of antipsychotic use [21]. Furthermore, the initiation of neuroleptics is associated with a 40 % increased risk of a fracture. Delirium is known to be a strong risk factor for dementia, and delirium accelerates cognitive decline in Alzheimer’s dementia [22, 23]. In light of this, haloperidol should be prescribed carefully, especially in the absence of scientific medical evidence. A key strength of this study is the use of a large hospital population dataset analyzed over a 1-year period, providing sufficient power for our study’s conclusions. Additionally, electronic records are a reliable way to capture medication use in a hospital setting. Some limitations should be acknowledged. The study was retrospective; we did not prospectively collect data on indications for haloperidol use. Retrospective analysis of medical charts could yield more relevant information. For example, indications for prescription, such as behavioral disorder or psychotic disorder, could not be taken into account because this detailed information was missing. Furthermore, the study of adverse events in relation to haloperidol use was beyond the scope of this study. Moreover, we limited this study to haloperidol users and did not investigate other atypical antipsychotics. However, in the Netherlands, haloperidol is the first medication of choice for the treatment of delirium in elderly patients in hospital [17].
5 Conclusion This study indicates that substantial numbers of older patients undergoing procedures are prescribed haloperidol, with an overall frequency of 5.4 %. The highest use is in older patients undergoing major or acute procedures. This
study is the first study to evaluate the use of haloperidol in a large hospital population with various surgical procedures. It is important because of the lack of strong positive evidence in favor of haloperidol use in the treatment of delirium and/or other indications (e.g., behavioral disturbance in dementia), and the potential adverse effects associated with this drug. Given the large-scale use of haloperidol, further research on the benefits, side effects, and costs of this treatment is urgently required. Compliance with ethical standards Conflict of interest None of the authors (Prof. A. McLullich, B.C. van Munster, G. Lefeber, H Nijboer) has any conflicts of interest that are directly relevant to the content of this study. Funding No sources of funding were used to assist in the preparation of this study. Ethical approval
Ethical approval was not required for this study.
Open Access This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
References 1. Administration F and D. www.fda.gov/Safety/MedWatch/ SafetyInformation/SafetyAlertsforHumanMedicalProducts/ ucm110212. Antipsychotics conventional and atypical. 2012. 2. Mittal V, Kurup L, Williamson D, Muralee S, Tampi RR. Risk of cerebrovascular adverse events and death in elderly patients with dementia when treated with antipsychotic medications: a literature review of evidence. Am J Alzheimers Dis Other Demen. 2011;26(1):10–28. 3. Pratt N, Roughead EE, Salter A, Ryan P. Choice of observational study design impacts on measurement of antipsychotic risks in the elderly: a systematic review. BMC Med Res Methodol. 2012;12:72.
88 4. Meyer-Massetti C, Vaerini S, Ra¨tz Bravo AE, Meier CR, Guglielmo BJ. Comparative safety of antipsychotics in the WHO pharmacovigilance database: the haloperidol case. Int J Clin Pharm. 2011;33(5):806–14. 5. Grover S, Mattoo SK, Gupta N. Usefulness of atypical antipsychotics and choline esterase inhibitors in delirium: a review. Pharmacopsychiatry. 2011;44(2):43–54. 6. Murray C, Sanderson DJ, Barkus C, Deacon RMJ, Rawlins JNP, Bannerman DM, et al. Systemic inflammation induces acute working memory deficits in the primed brain: relevance for delirium. Neurobiol Aging. 2012;33(3):603–16. 7. Bilotta F, Lauretta MP, Borozdina A, Mizikov VM, Rosa G. Postoperative delirium: risk factors, diagnosis and perioperative care. Minerva Anestesiol. 2013;79(9):1066–76. 8. Searle SD, Mitnitski A, Gahbauer EA, Gill TM, Rockwood K. A standard procedure for creating a frailty index. BMC Geriatr. 2008;8(1):24. 9. Morandi A, Davis D, Taylor JK, Bellelli G, Olofsson B, Kreisel S, et al. Consensus and variations in opinions on delirium care: a survey of European delirium specialists. Int Psychogeriatr. 2013;25(12):2067–75. 10. Hipp DM, Ely EW. Pharmacological and nonpharmacological management of delirium in critically ill patients. Neurotherapeutics. 2012;9(1):158–75. 11. Yoon H-J, Park K-M, Choi W-J, Choi S-H, Park J-Y, Kim J-J, et al. Efficacy and safety of haloperidol versus atypical antipsychotic medications in the treatment of delirium. BMC Psychiatry. 2013;13:240. 12. Maneeton B, Maneeton N, Srisurapanont M, Chittawatanarat K. Quetiapine versus haloperidol in the treatment of delirium: a double-blind, randomized, controlled trial. Drug Des Devel Ther. 2013;7:657–67. 13. Han C-S, Kim Y-K. A double-blind trial of risperidone and haloperidol for the treatment of delirium. Psychosomatics. 2004;45(4):297–301.
H. Nijboer 14. Tagarakis GI, Voucharas C, Tsolaki F, Daskalopoulos ME, Papaliagkas V, Parisis C, et al. Ondasetron versus haloperidol for the treatment of postcardiotomy delirium: a prospective, randomized, double-blinded study. J Cardiothorac Surg. 2012;7:25. 15. Grover S, Kumar V, Chakrabarti S. Comparative efficacy study of haloperidol, olanzapine and risperidone in delirium. J Psychosom Res. 2011;71(4):277–81. 16. Management C, The OF, Patient G. American geriatrics society abstracted clinical practice guideline for postoperative delirium in older adults. J Am Geriatr Soc. 2015;63(1):142–50. 17. Leentjens AFG, Molag ML, Van Munster BC, De Rooij SE, Luijendijk HJ, Vochteloo AJH, et al. Changing perspectives on delirium care: the new Dutch guideline on delirium. J Psychosom Res. 2014;77(3):240–1. 18. Noimark D. Predicting the onset of delirium in the post-operative patient. Age Ageing. 2009;38(4):368–73. 19. Rudolph JL, Marcantonio ER. Review articles: postoperative delirium: acute change with long-term implications. Anesth Analg. 2011;112(5):1202–11. 20. Knol W, van Marum RJ, Jansen PAF, Souverein PC, Schobben AFAM, Egberts ACG. Antipsychotic drug use and risk of pneumonia in elderly people. J Am Geriatr Soc. 2008;56(4):661–6. 21. Kleijer BC, van Marum RJ, Egberts ACG, Jansen PAF, Knol W, Heerdink ER. Risk of cerebrovascular events in elderly users of antipsychotics. J Psychopharmacol. 2009;23(8):909–14. 22. Davis DHJ, Muniz Terrera G, Keage H, Rahkonen T, Oinas M, Matthews FE, et al. Delirium is a strong risk factor for dementia in the oldest-old: a population-based cohort study. Brain. 2012;135(Pt 9):2809–16. 23. Fong TG, Jones RN, Shi P, Marcantonio ER, Yap L, Rudolph JL, et al. Delirium accelerates cognitive decline in Alzheimer disease. Neurology. 2009;72(18):1570–5.
ORIGINAL RESEARCH ARTICLE
Haloperidol Use Among Elderly Patients Undergoing Surgery: A Retrospective 1-Year Study in a Hospital Population Harmke Nijboer1 • Geert Lefeber1 • Alidair McLullich1 • Barbara van Munster1
Published online: 3 March 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com
Abstract Background Haloperidol, frequently used for delirium, can lead to serious side effects, of which QTc prolongation is the most worrisome since it is associated with an increased risk of fatal cardiac arrhythmia. Objectives The aim of this study was to measure the frequency of haloperidol use after procedures in patients aged C65 years in a hospital in the Netherlands. Methods This was a retrospective study among patients hospitalized in the Netherlands who were aged C65 years and who underwent a procedure between January 2008 and January 2009. The hospital’s electronic drug database was used to identify the use of haloperidol during hospital admission. Results A total of 7782 procedures took place in 5946 elderly patients, and 1357 patients were readmitted for a second procedure in the same year. The overall frequency of haloperidol use was 5.4 %. Procedures were classified as elective (90 %) and as major (18 %). A total of 28 % (n = 570) of patients who underwent acute procedures and 24 % (n = 1086) of patients who underwent major procedures received haloperidol. Patients receiving haloperidol had a significantly longer hospital stay (14 vs. 1 day, p \ 0.001) than patients without haloperidol. Haloperidol users were more likely to have more than one intervention than nonusers (16.0 vs. 1.7 %, p \ 0.001). In multivariable analysis, haloperidol use was associated with older age (odds ratio [OR] 1.09; 95 % confidence interval [CI] 1.07–1.11, p \ 0.001), acute surgery (OR 2.09; 95 % CI 1.65–2.94,
& Harmke Nijboer [email protected] 1
Catharina Hospital, Eindhoven, Brabant, The Netherlands
p \ 0.001), and major procedures (OR 15.4; 95 % CI 11.5–21.5, p \ 0.001). Conclusion We show a frequency of haloperidol use of 5.4 %. Based on this high frequency, surveillance of adverse events in hospital should be performed systematically, particularly in the high-risk population that undergoes acute major surgery.
Key Points The frequency of haloperidol use among hospitalized patients in the Netherlands aged C65 years who underwent a procedure between January 2008 and January 2009 was over 5 %. The percentage of haloperidol users is higher in older patients undergoing acute or major procedures. Patients using haloperidol experienced a longer hospital stay in this study and are known to have a higher risk of adverse events in the literature.
1 Introduction In 2005, the US FDA warned clinicians against prescribing antipsychotic medications to patients with dementia-related psychosis, because it would expose patients to an increased risk of death [1]. Mittal et al. [2] showed a 1.3 to 2.0-fold increased risk of stroke and a 1.2 to 1.6-fold increased risk of mortality; these risk ratios are comparable for all antipsychotics. Known immediate side effects of antipsychotics include somnolence, urinary tract infection, urinary
84
incontinence, extrapyramidal symptoms, or abnormal gait [3–6]. Antipsychotics are prescribed for many different symptoms and diseases, such as anxiety, psychosis due to schizophrenic disease or depression, and behavioral disturbance in dementia or delirium. Hospitalized patients with delirium may have a similar or even higher potential for adverse side effects from antipsychotics than more stable patients. The most important known risk factors for postoperative delirium are older age and cognitive or functional impairment [7]. Many older patients with delirium also have dementia; they also usually have an acute medical illness and multiple comorbidities, and are often taking drugs that increase the QTc interval. Yet this issue remains unaddressed, because no published, adequately powered, double-blind, randomized, placebo-controlled trials have examined the safety of antipsychotics in the management of delirium [8]. In addition, no specific recommendations exist for patients with delirium as well as dementia. Prevalence estimates for delirium during a hospital admission are 10–30 %; thus, it is reasonable to assume that this condition is the single most common cause for the administration of haloperidol in a hospital setting [9, 10]. The scientific evidence for the efficacy of haloperidol in treating delirium is based on a few studies [10]. Five studies evaluated the side effects of haloperidol versus various neuroleptics (e.g., risperidone, olanzapine, quetiapine, and ondansetron) and showed no significant differences in the treatment response for delirium symptoms [11–15]. The 2010 UK National Institute for Health and Care Excellence (NICE) guideline on delirium, which took into account the evidence available at that time, advised limiting the use of antipsychotics for individuals with delirium in distress or at risk to themselves or others. Furthermore, it should be prescribed only after nonpharmacological interventions have been tried, and then only in the lowest possible dose and for the shortest possible time period [16]. The aim of this study was to measure the frequency of haloperidol use after procedures in patients aged C65 years in a hospital in the Netherlands. A prerequisite for assessing the risks associated with antipsychotic use in hospitalized patients is to have systems that record the use of these drugs. To address the above gap in the literature, we used electronic pharmacy records to determine the proportion of hospitalized patients aged C65 years administered haloperidol after surgical procedures. We studied haloperidol because it is the first-choice medication for delirium in the Netherlands [17].
H. Nijboer
2 Methods 2.1 Patients All patients aged C65 years who underwent a surgical procedure in the Jeroen Bosch hospital in s–Hertogenbosch in the Netherlands in the period between 1 January 2008 and 1 January 2009 were included. This hospital has 750 beds and is a non-academic, regional teaching hospital with 21 separate medical training specialties. The surgical specialties were gynecology, orthopedics, general surgery, urology, ophthalmology, otorhinolaryngology, oral surgery, neurosurgery, and plastic or reconstructive surgery. 2.2 Study Design Haloperidol administration during admission was identified using the electronic hospital drug database. Inclusion criteria included patients who took this medication for at least 1 day during their admission period. In the Netherlands, the conventional starting dose for haloperidol is 1 mg. Minor procedures were defined as procedures for which patients were admitted for less than 6 days, and major procedures were defined as a stay longer than 6 days. Procedures were categorized as either acute or elective based on the reason for admission, as classified by the International Statistical Classification of Diseases and Related Health Problems – 9th revision (ICD-9). 2.3 Statistical Analysis We used the Statistical Package for the Social Sciences (SPSS, version 19.0, Chicago, IL, USA) for data analysis. We used t-tests and Mann–Whitney U tests to test for differences in characteristics in patients with and without haloperidol use. Variables that were not normally distributed were expressed as median scores and interquartile ranges. A two-tailed criterion of p \ 0.05 was considered statistically significant. We performed univariate and multivariate logistic regression analyses, where haloperidol use was the dependent variable, and age, acute versus elective surgery, minor versus major procedures, and surgical specialty were the independent variables.
3 Results A total of 7782 procedures occurred in 5946 patients; 145 patients underwent a second procedure during their first admission, and 1357 patients were admitted for at least one additional procedure in the same year. The characteristics of the patients who did and did not use haloperidol are
Haloperidol Use Among Elderly Patients Undergoing Surgery
85
presented in Table 1. The overall incidence of haloperidol use related to the first procedure in the first admission was 5.4 %. Of these, 323 patients (12 %) received haloperidol throughout the complete admission period. Those administered haloperidol were significantly older (81.2 vs. 74.4 years, p \ 0.001). In acute procedures (n = 570), the percentage of haloperidol use was 28.0 versus 3.1 % in the 5376 elective procedures (p \ 0.001). In major procedures (n = 1086), the percentage was 24.0 versus 1.3 % in 4960 minor procedures (p \ 0.001). Patients who received haloperidol had a significantly longer hospital stay (14 vs. 1 day, p \ 0.001) than patients who did not receive haloperidol. Haloperidol users more often underwent more than one procedure (e.g., they underwent two operations or a biopsy followed by an operation during the admission period [16.0 vs. 1.7 %, p \ 0.001]) than non-users, but they were less frequently readmitted for a second procedure (12 vs. 23 %, p \ 0.001). An overview of the most common procedures per specialty is presented in Table 2; 90 % of procedures were elective and 18 % were major. A total of 29 % of acute procedures and 45 % of major procedures were performed in general surgery. Of these, 15 % of patients received haloperidol. Ophthalmologic surgery was the most frequent type of surgery (n = 1865; 31.4 %), and the majority of the ophthalmologic interventions were cataract operations (89.5 %). These were classified as minor procedures, with a haloperidol usage of 0.4 %. Haloperidol use in patients admitted with a fracture was acute: 30 % in surgical Table 1 Characteristics of patients who did and did not receive haloperidol
Variables
patients and 34 % in orthopedic patients. Haloperidol use in orthopedics was 6.4 %, in plastic surgery 0.3 %, in urology 2.4 %, and in gynecology 1.7 %; no patients in the otorhinolaryngology received haloperidol. The odds ratio (OR) of haloperidol administration upon second admission if patients had already been administered haloperidol at first admission was 55 (95 % confidence interval [CI] 27–116). Table 3 shows the results of the multivariate analysis. Haloperidol use was strongly associated with specialty, specifically general surgery (OR 6.4, 95 % CI 4.0–10.1, p \ 0.001), acute procedures (OR 1.5, 95 % CI 1.1–2.1, p \ 0.001), major procedures (OR 8.3, 95 % CI 5.9–11.5, p \ 0.001), and older age (OR 1.1, 95 % CI 1.08–1.12, p \ 0.001).
4 Discussion In this descriptive study of haloperidol use in a hospital population of surgical patients (N = 5946) treated over the course of 1 year in a single large hospital in the Netherlands, we found an overall frequency of haloperidol administration of 5.4 %. The hospital is representative of large teaching hospitals in the Netherlands. Haloperidol use in acute and major surgery was much higher than in elective and minor surgery; at least one-quarter of patients who fell into either category received this drug. The fact that haloperidol administration was associated with older age, acute procedures, and major procedures, which are all
Haloperidol (N = 323)
No haloperidol (N = 5623)
p value \0.001
Age (years)
81.2 (65–101)
74.4 (65–104)
Male sex (%)
145 ± 45
2409 ± 43
Ophthalmology
7 ± 2.2
1858 ± 33
General surgery Orthopedic surgery
230 ± 71 66 ± 20
1269 ± 23 962 ± 17
Plastic surgery
2 ± 0.6
632 ± 11
0.47 \0.001
Specialty (%)
Urology
14 ± 4.3
578 ± 10
Gynaecology
4 ± 1.2
226 ± 4.0
Otorhinolaryngology
0±0
70 ± 1.2
Othera
0±0
28 ± 0.5
Acute procedure (%)
157 ± 49
413 ± 7.3
\0.001
Major procedure (%)
261 ± 81
825 ± 15
\0.001
Length of stay
14 (2–133)
1 (1–142)
\0.001
C1 Intervention (%)
52 ± 16
93 ± 1.7
\0.001
C1 Admission (%)
39 ± 12
1318 ± 23
\0.001
Data are presented as mean ± standard deviation for continuous variables with a normal distribution or as median (interquartile range) for variables that are not normally distributed a
‘Other’ includes cardiology, neurosurgery, and oral surgery
86 Table 2 Characteristics of the most common surgical procedures, by specialty
H. Nijboer
Variables
Procedures
Acute (%)
Ophthalmology
1865
1 (0.1)
Senile cataract
1670 (89.5 %)
General
1499
Fracture reposition
318 (21.2 %)
Biopsya
240 (16 %)
Digestive tract operations
218 (14.6 %)
Vascular intervention
200 (13.3 %)
Inguinal hernia operation
140 (9.3 %)
Shunt construction
38 (2.5 %)
Orthopedics
1028
Osteoarthrosis surgery
86 (8.4 %)
Removal of plates and correction material
83 (8 %)
Hand surgery due to mononeuritis Biopsy
634
54 (8.5 %)
Other
386 (60.9 %) 592
Urethrocystoscopy
320 (54.1 %)
Prostatectomy
138 (23.3 %)
Biopsy
34 (5.4 %)
Gynecology
230
Biopsy
91(39.6 %)
Genital prolapse surgery
78 (33.9 %)
Otorhinolaryngology
70
Sinusitis surgery
20 (28.6 %)
Septum rhinoplasty
8 (11.4 %)
Correction nasal polyp Otherb
0.4 %
430 (29)
674 (45)
15.3 %
110 (11)
250 (24)
6.4 %
8 (1.3)
16 (2.5)
0.3 %
15 (2.5)
70 (12)
2.4 %
3 (1.3)
69 (30)
1.7 %
124 (19.6 %) 36 (5.4 %)
Eye correction surgery Urology
3 (0.2)
Haloperidol Use
478 (46.5 %)
Fracture reposition Plastic surgery
Major (%)
0
1 (1.4)
0
3 (11)
3 (11)
0
9 (12.9 %) 28
a
Biopsy in general surgery includes pulmonary biopsy, lymph nodular explorations, benign exploration of thyroid pathology, rectal polyp excisions, and mamma incision biopsy
b
‘Other’ includes neurosurgery and oral surgery
established risk factors for delirium, suggests that delirium could be the most important indication for its prescription [18]. However, we do not know the indication of haloperidol use, and the known risk factors for delirium— such as operative stress and other drugs used peri- and postoperatively—are not measured in our database. Furthermore, in our study population, a large group of patients were ophthalmologic patients (n = 1865), most of whom underwent a cataract procedure; this type of procedure is known to have a low delirium prevalence. It is possible that approximately 0.1 % of patients received haloperidol 1 mg/day prior to procedures if it was known that they had a medical history of serious delirium. Indeed, a 5.4 % haloperidol administration level is consistent with the typical delirium rates in these groups, as
reported in the international literature [16, 17]. Additionally, the multivariate analysis showed that haloperidol use was associated with longer hospital stay, which might be another indirect clue that patients who received haloperidol experienced delirium because delirium is known to be associated with a prolonged hospital stay [19]. Alternatively, the use of haloperidol itself may have contributed to the length of stay. More broadly, this study shows that large numbers of older people received haloperidol during their hospitalisation for surgery. This level of haloperidol use is notable given the lack of strong evidence for the benefits of this drug in the treatment of delirium. No previous study has investigated the appropriate antipsychotic dosage levels for delirium, and we believe different countries have different antipsychotic dosage strategies [9].
Haloperidol Use Among Elderly Patients Undergoing Surgery
87
Table 3 Univariate and multivariate analysis of the factors associated with haloperidol use in surgical patients aged [65 years Factor
Univariate analysis OR (95 % CI)
p value
Multivariate analysis OR (95 % CI)
p value
Age (years)
1.12 (1.11–1.14)
\0.001
1.1 (1.08–1.12)
\0.001
Specialty (%) Othera
Reference
General surgery
22.8 (15.2–34.1)
\0.001
6.4 (4.0–10.1)
\0.001
Orthopedic surgery
8.6 (5.5–13.6)
\0.001
4.0 (2.4–6.5)
\0.001
Acute procedure (%)
11.9 (9.38–15.2)
\0.001
Major procedure (%)
24.5 (18.4–32.6)
0.004
1.5 (1.1–2.1)
\0.001
8.3 (5.9–11.5)
\0.001
CI confidence interval, OR odds ratio a
All surgeries except general or orthopedic surgery
Importantly, in the last 10 years, more studies have identified a number of risks associated with prescribing antipsychotic drugs during hospital stay, such as a higher risk of pneumonia [20] and or cerebrovascular events. This risk is present even during the first week of antipsychotic use [21]. Furthermore, the initiation of neuroleptics is associated with a 40 % increased risk of a fracture. Delirium is known to be a strong risk factor for dementia, and delirium accelerates cognitive decline in Alzheimer’s dementia [22, 23]. In light of this, haloperidol should be prescribed carefully, especially in the absence of scientific medical evidence. A key strength of this study is the use of a large hospital population dataset analyzed over a 1-year period, providing sufficient power for our study’s conclusions. Additionally, electronic records are a reliable way to capture medication use in a hospital setting. Some limitations should be acknowledged. The study was retrospective; we did not prospectively collect data on indications for haloperidol use. Retrospective analysis of medical charts could yield more relevant information. For example, indications for prescription, such as behavioral disorder or psychotic disorder, could not be taken into account because this detailed information was missing. Furthermore, the study of adverse events in relation to haloperidol use was beyond the scope of this study. Moreover, we limited this study to haloperidol users and did not investigate other atypical antipsychotics. However, in the Netherlands, haloperidol is the first medication of choice for the treatment of delirium in elderly patients in hospital [17].
5 Conclusion This study indicates that substantial numbers of older patients undergoing procedures are prescribed haloperidol, with an overall frequency of 5.4 %. The highest use is in older patients undergoing major or acute procedures. This
study is the first study to evaluate the use of haloperidol in a large hospital population with various surgical procedures. It is important because of the lack of strong positive evidence in favor of haloperidol use in the treatment of delirium and/or other indications (e.g., behavioral disturbance in dementia), and the potential adverse effects associated with this drug. Given the large-scale use of haloperidol, further research on the benefits, side effects, and costs of this treatment is urgently required. Compliance with ethical standards Conflict of interest None of the authors (Prof. A. McLullich, B.C. van Munster, G. Lefeber, H Nijboer) has any conflicts of interest that are directly relevant to the content of this study. Funding No sources of funding were used to assist in the preparation of this study. Ethical approval
Ethical approval was not required for this study.
Open Access This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
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